TY - JOUR

T1 - Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

AU - Mullins, Niamh

AU - Kang, Joo Eun

AU - Campos, Adrian I.

AU - Coleman, Jonathan R.I.

AU - Edwards, Alexis C.

AU - Galfalvy, Hanga

AU - Levey, Daniel F.

AU - Lori, Adriana

AU - Shabalin, Andrey

AU - Starnawska, Anna

AU - Su, Mei Hsin

AU - Watson, Hunna J.

AU - Adams, Mark

AU - Awasthi, Swapnil

AU - Gandal, Michael

AU - Hafferty, Jonathan D.

AU - Hishimoto, Akitoyo

AU - Kim, Minsoo

AU - Okazaki, Satoshi

AU - Otsuka, Ikuo

AU - Ripke, Stephan

AU - Ware, Erin B.

AU - Bergen, Andrew W.

AU - Berrettini, Wade H.

AU - Bohus, Martin

AU - Brandt, Harry

AU - Chang, Xiao

AU - Chen, Wei J.

AU - Chen, Hsi Chung

AU - Crawford, Steven

AU - Crow, Scott

AU - DiBlasi, Emily

AU - Duriez, Philibert

AU - Fernández-Aranda, Fernando

AU - Fichter, Manfred M.

AU - Gallinger, Steven

AU - Glatt, Stephen J.

AU - Gorwood, Philip

AU - Guo, Yiran

AU - Hakonarson, Hakon

AU - Halmi, Katherine A.

AU - Hwu, Hai Gwo

AU - Jain, Sonia

AU - Li, Dong

AU - Røpke, Stefan

AU - Appadurai, Vivek

AU - Jonsson, Lina

AU - Schofield, Peter R.

AU - Nordentoft, Merete

AU - Werge, Thomas

AU - VA Million Veteran Program

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

AU - Eating Disorders Working Group of the Psychiatric Genomics Consortium

AU - German Borderline Genomics Consortium

AU - MVP Suicide Exemplar Workgroup

N1 - Publisher Copyright: Copyright © 2021 Society of Biological Psychiatry. All rights reserved.

PY - 2022

Y1 - 2022

N2 - BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

AB - BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

KW - Genetic correlation

KW - Genome-wide association study

KW - Pleiotropy

KW - Polygenicity

KW - Suicide

KW - Suicide attempt

U2 - 10.1016/j.biopsych.2021.05.029

DO - 10.1016/j.biopsych.2021.05.029

M3 - Journal article

C2 - 34861974

AN - SCOPUS:85119273569

VL - 91

SP - 313

EP - 327

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 3

ER -